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J Biol Chem, Vol. 274, Issue 45, 31917-31924, November 5, 1999
From the Department of Pharmacology, The University of Texas
Southwestern Medical Center, Dallas, Texas 75235-9041
The function of the retinoblastoma protein (pRB)
in controlling the G1 to S transition is regulated by
phosphorylation and dephosphorylation on serine and threonine residues.
While the roles of cyclin-dependent kinases in
phosphorylating and inactivating pRB have been characterized in detail,
the roles of protein phosphatases in regulating the G1/S
transition are not as well understood. We used cell-permeable
inhibitors of protein phosphatases 1 and 2A to assess the contributions
of these phosphatases in regulating cyclin-dependent kinase
activity and pRB phosphorylation. Treating asynchronously growing
Balb/c 3T3 cells with PP2A-selective concentrations of either okadaic
acid or calyculin A caused a time- and dose-dependent decrease in pRB phosphorylation. Okadaic acid and calyculin A had no
effect on pRB phosphatase activity even though PP2A was completely
inhibited. The decrease in pRB phosphorylation correlated with
inhibitor-induced suppression of G1
cyclin-dependent kinases including CDK2, CDK4, and CDK6.
The inhibitors also caused decreases in the levels of cyclin D2 and
cyclin E, and induction of the cyclin-dependent kinase
inhibitors p21Cip1 and p27Kip1. The decrease in
cyclin-dependent kinase activities were not dependent on
induction of cyclin-dependent kinase inhibitors since CDK
inhibition still occurred in the presence of actinomycin D or
cycloheximide. In contrast, selective inhibition of protein phosphatase
1 with tautomycin inhibited pRB phosphatase activity and maintained pRB
in a highly phosphorylated state. The results show that protein
phosphatase 1 and protein phosphatase 2A, or 2A-like phosphatases, play
distinct roles in regulating pRB function. Protein phosphatase 1 is
associated with the direct dephosphorylation of pRB while protein
phosphatase 2A is involved in pathways regulating G1
cyclin-dependent kinase activity.
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